Genetic Variant SIGLEC1:p.His919Pro (chr20-3694851-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_023068.4(SIGLEC1):c.2756A>C(p.His919Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,613,124 control chromosomes in the GnomAD database, including 334,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.69 ( 36578 hom., cov: 33)

Exomes 𝑓: 0.63 ( 297517 hom. )

Consequence

SIGLEC1
NM_023068.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.92

Variant links:

Genes affected

SIGLEC1 (HGNC:11127): (sialic acid binding Ig like lectin 1) This gene encodes a member of the immunoglobulin superfamily. The encoded protein is a lectin-like adhesion molecule that binds glycoconjugate ligands on cell surfaces in a sialic acid-dependent manner. It is a type I transmembrane protein expressed only by a subpopulation of macrophages and is involved in mediating cell-cell interactions. The protein plays an important role in multiple human diseases and bacterial and viral infections has been shown to enhance SARS-CoV-2 infection. [provided by RefSeq, Dec 2021]

SIGLEC1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.4370726E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC1	NM_023068.4 link	c.2756A>C	p.His919Pro	missense_variant	Exon 12 of 22	ENST00000344754.6	NP_075556.1	Q9BZZ2-1
SIGLEC1	NM_001367089.1 link	c.2756A>C	p.His919Pro	missense_variant	Exon 11 of 20		NP_001354018.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC1	ENST00000344754.6 link	c.2756A>C	p.His919Pro	missense_variant	Exon 12 of 22	1	NM_023068.4	ENSP00000341141.4		Q9BZZ2-1
SIGLEC1	ENST00000707083.1 link	c.2756A>C	p.His919Pro	missense_variant	Exon 11 of 20			ENSP00000516734.1		Q9BZZ2-3

Frequencies

GnomAD3 genomes

AF:

0.688

AC:

104664

AN:

152046

Hom.:

36535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.777

Gnomad AMI

AF:

0.386

Gnomad AMR

AF:

0.694

Gnomad ASJ

AF:

0.575

Gnomad EAS

AF:

0.863

Gnomad SAS

AF:

0.698

Gnomad FIN

AF:

0.760

Gnomad MID

AF:

0.567

Gnomad NFE

AF:

0.619

Gnomad OTH

AF:

0.661

GnomAD3 exomes

AF:

0.686

AC:

171833

AN:

250518

Hom.:

59770

AF XY:

0.679

AC XY:

92139

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.782

Gnomad AMR exome

AF:

0.746

Gnomad ASJ exome

AF:

0.583

Gnomad EAS exome

AF:

0.875

Gnomad SAS exome

AF:

0.681

Gnomad FIN exome

AF:

0.760

Gnomad NFE exome

AF:

0.621

Gnomad OTH exome

AF:

0.654

GnomAD4 exome

AF:

0.635

AC:

927687

AN:

1460960

Hom.:

297517

Cov.:

AF XY:

0.636

AC XY:

462328

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.780

Gnomad4 AMR exome

AF:

0.740

Gnomad4 ASJ exome

AF:

0.587

Gnomad4 EAS exome

AF:

0.826

Gnomad4 SAS exome

AF:

0.681

Gnomad4 FIN exome

AF:

0.751

Gnomad4 NFE exome

AF:

0.611

Gnomad4 OTH exome

AF:

0.648

GnomAD4 genome

AF:

0.688

AC:

104756

AN:

152164

Hom.:

36578

Cov.:

AF XY:

0.697

AC XY:

51854

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.777

Gnomad4 AMR

AF:

0.695

Gnomad4 ASJ

AF:

0.575

Gnomad4 EAS

AF:

0.863

Gnomad4 SAS

AF:

0.698

Gnomad4 FIN

AF:

0.760

Gnomad4 NFE

AF:

0.619

Gnomad4 OTH

AF:

0.656

Alfa

AF:

0.628

Hom.:

76021

Bravo

AF:

0.685

TwinsUK

AF:

0.605

AC:

2243

ALSPAC

AF:

0.610

AC:

2352

ESP6500AA

AF:

0.766

AC:

3376

ESP6500EA

AF:

0.615

AC:

5293

ExAC

AF:

0.682

AC:

82829

Asia WGS

AF:

0.755

AC:

2626

AN:

3478

EpiCase

AF:

0.610

EpiControl

AF:

0.609

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.031

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Benign

0.044

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.10

MetaRNN

Benign

8.4e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.4

PrimateAI

Benign

0.41

PROVEAN

Benign

0.92

REVEL

Benign

0.073

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MPC

0.17

ClinPred

0.011

GERP RS

4.8

Varity_R

0.14

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over